Integration of rare expression outlier-associated variants improves polygenic risk prediction

Polygenic risk scores (PRSs) quantify the contribution of multiple genetic loci to an individual's likelihood of a complex trait or disease. However, existing PRSs estimate this likelihood with common genetic variants, excluding the impact of rare variants. Here, we report on a method to identi...

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Vydáno v:American journal of human genetics Ročník 109; číslo 6; s. 1055
Hlavní autoři: Smail, Craig, Ferraro, Nicole M, Hui, Qin, Durrant, Matthew G, Aguirre, Matthew, Tanigawa, Yosuke, Keever-Keigher, Marissa R, Rao, Abhiram S, Justesen, Johanne M, Li, Xin, Gloudemans, Michael J, Assimes, Themistocles L, Kooperberg, Charles, Reiner, Alexander P, Huang, Jie, O'Donnell, Christopher J, Sun, Yan V, Rivas, Manuel A, Montgomery, Stephen B
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 02.06.2022
Témata:
Body Mass Index
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Multifactorial Inheritance - genetics
Obesity - genetics
Phenotype
Risk Factors
rare variants
transcriptomics
complex disease
obesity
BMI
polygenic risk scores
ISSN:1537-6605, 1537-6605
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Shrnutí:Polygenic risk scores (PRSs) quantify the contribution of multiple genetic loci to an individual's likelihood of a complex trait or disease. However, existing PRSs estimate this likelihood with common genetic variants, excluding the impact of rare variants. Here, we report on a method to identify rare variants associated with outlier gene expression and integrate their impact into PRS predictions for body mass index (BMI), obesity, and bariatric surgery. Between the top and bottom 10%, we observed a 20.8% increase in risk for obesity (p = 3 × 10 ), 62.3% increase in risk for severe obesity (p = 1 × 10 ), and median 5.29 years earlier onset for bariatric surgery (p = 0.008), as a function of expression outlier-associated rare variant burden when controlling for common variant PRS. We show that these predictions were more significant than integrating the effects of rare protein-truncating variants (PTVs), observing a mean 19% increase in phenotypic variance explained with expression outlier-associated rare variants when compared with PTVs (p = 2 × 10 ). We replicated these findings by using data from the Million Veteran Program and demonstrated that PRSs across multiple traits and diseases can benefit from the inclusion of expression outlier-associated rare variants identified through population-scale transcriptome sequencing.
Bibliografie:ObjectType-Article-1
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ISSN:1537-6605
1537-6605
DOI:10.1016/j.ajhg.2022.04.015